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<p>Genetic studies have linked <i>EPHX2</i> (encoding soluble epoxide hydrolase, sEH) and <i>PTGS2</i> (encoding cyclooxygenase-2, COX-2) to Alzheimer’s disease (AD). Elevated levels of sEH and COX-2 found in AD patients and animals suggest their involvement in neurodegeneration, glial activation, vascular dysfunction, and inflammation. This study evaluated the effects of a new dual sEH/COX-2 inhibitor, PTUPB, on cerebrovascular function and cognition in TgF344-AD rats. The rats received oral PTUPB (2&#xa0;mg/kg/day) for 25&#xa0;days. Body weight, plasma glucose, and HbA1c levels remained stable between PTUPB- and vehicle-treated AD rats. PTUPB significantly improved recognition memory in AD rats, as detected by the novel object recognition test. Pressure myography showed that PTUPB restored myogenic responses and increased the distensibility of the middle cerebral arteries (MCAs) in AD rats. Acute PTUPB (0.1 and 1&#xa0;μM) enhanced myogenic contraction in response to elevated perfusion pressure in AD MCAs, with minimal effects in wild-type vessels. Transcriptomic analysis of cerebral vascular smooth muscle cells from AD rats revealed that PTUPB influences genes involved in contractility, extracellular matrix remodeling, inflammation, and oxidative stress. These results provide new evidence that dual inhibition of sEH and COX-2 improves cognition in AD and is associated with enhanced myogenic response via attenuation of vascular remodeling. Our findings highlight the potential of PTUPB as a therapeutic approach for cerebrovascular dysfunction in AD.</p>

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PTUPB improves cognitive function in Alzheimer’s disease associated with enhancing cerebral vascular myogenic response and attenuating vascular remodeling

  • 期刊论文

  • 发表日期：

    2026年2月6日

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  • Gilbert C. Morgan,
  • Andrew Gregory,
  • Chengyun Tang,
  • Sung Hee Hwang,
  • Jane J. Border,
  • Jing Xu,
  • Yedan Liu,
  • Shan Bai,
  • Tae Jin Lee,
  • Cameron Cantwell,
  • David Bunn,
  • Karen M. Wagner,
  • Christophe Morisseau,
  • Carly Pittman,
  • Alina Ngo,
  • Peter Osayi,
  • Aditi Pabbidi,
  • Philip O’Herron,
  • Zsolt Bagi,
  • Jessica A. Filosa,
  • Hongwei Yu,
  • Cindy McReynolds,
  • Bruce D. Hammock,
  • Richard J. Roman,
  • Fan Fan

摘要

Genetic studies have linked EPHX2 (encoding soluble epoxide hydrolase, sEH) and PTGS2 (encoding cyclooxygenase-2, COX-2) to Alzheimer’s disease (AD). Elevated levels of sEH and COX-2 found in AD patients and animals suggest their involvement in neurodegeneration, glial activation, vascular dysfunction, and inflammation. This study evaluated the effects of a new dual sEH/COX-2 inhibitor, PTUPB, on cerebrovascular function and cognition in TgF344-AD rats. The rats received oral PTUPB (2 mg/kg/day) for 25 days. Body weight, plasma glucose, and HbA1c levels remained stable between PTUPB- and vehicle-treated AD rats. PTUPB significantly improved recognition memory in AD rats, as detected by the novel object recognition test. Pressure myography showed that PTUPB restored myogenic responses and increased the distensibility of the middle cerebral arteries (MCAs) in AD rats. Acute PTUPB (0.1 and 1 μM) enhanced myogenic contraction in response to elevated perfusion pressure in AD MCAs, with minimal effects in wild-type vessels. Transcriptomic analysis of cerebral vascular smooth muscle cells from AD rats revealed that PTUPB influences genes involved in contractility, extracellular matrix remodeling, inflammation, and oxidative stress. These results provide new evidence that dual inhibition of sEH and COX-2 improves cognition in AD and is associated with enhanced myogenic response via attenuation of vascular remodeling. Our findings highlight the potential of PTUPB as a therapeutic approach for cerebrovascular dysfunction in AD.